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Adoptive
Immunotherapy
Chris Cunningham & Asad Usman
Mathematical Biology 463
Dr. Jackson
The Basics
 What is the Immune Response?
• The immune response involves a
coordinated set of interactions among
host cells and the protective molecules
when they encountering a foreign
particle
 Purpose of Immune Response
• To prevent unhealthy states and to
restore homeostasis
 For example – Prevent Cancer: the
uncontrolled growth of cells in the body
The Basics - Background
 The most common treatment for cancer is
chemotherapy
 Chemotherapy, though helpful, also causes
unwanted side effects
 Chemotherapy focuses on irradiation of tumor
cells in order to decrease growth rate
 However, some natural cells have high growth
rate, such as the skin, the stomach, and mouth,
these cells can be adversely effected by
chemotherapy
 An alternative solution has developed called:
Adoptive Immunotherapy
The Basics - Introduction
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 What is Adoptive Immunotherapy:
• Its is a form of immunotherapy used in
the treatment of cancer
• An individual's own white blood cells
are coupled with a naturally produced
growth factor to enhance their cancerfighting capacity
• Then, these are injected into tumor site
to increase immune response locally
 Injections can be +/- Immune Cells and +/growth factor
Introduction to Model
 Our model has three key biological
components from the immune
system:
1. Effector Cells
2. Tumor Cells
3. Cytokines – Molecules that enhance
Effector Cells
 Specifically IL-2
Immune Response
 Acquired Immune Response
• Immunity mediated by lymphocytes and
characterized by antigen-specificity and
memory
 Cell Mediated - T lymphocytes (T cells)
 Adoptive – Therapy Injections
False-color scanning electron
micrograph of two lymphokineactivated killer (LAK) cells. In LAK
immunotherapy, a patient's
peripheral blood mononuclear
cells are removed and cultured
with interluekin-2 (IL-2) to allow
LAK cells to develop. (Photo
Science Library.)
Immune Biology
 Effector Cells
• T Lympocytes
 Lymphocytes express highly specific
ANTIGEN RECEPTORS on their surface
 Lymphocytes are highly specific for a
given structural motif
 Usually CD8+ cells which kill target cells by
recognizing foreign peptide-MHC molecules
on the target cell membrane.
• Model
 dE/dt = The Change in Effector cell pop.
over time
Immune Biology
 Tumors
• Cancer cells must express ANTIGENS (foreign
particles) recognizable and accessible to the
immune system. - Antigenicity
• The immune system must in turn be able to
mount a response against cells bearing such
antigens
• Tumors possess a varying degree of Immune
“Antigenicity” that is unique to each tumor and
thus be rejected by Immunocompetent hosts.
• Model
 dT/dt = The change in Tumor cell pop. over time
Immune Biology
 Cytokines
• Low molecular weight protein mediators
involved in cell growth, inflammation,
immunity, differentiation and repair
• Production triggered by presence of foreign
particles
 Autocrine agent – Act on cell that produced it
• Types
 Interleukins (ex. IL-2)
• Meaning: They are chemical messengers between
(inter) Leukocytes
 Interferons
• Model
 dI/dt = The Change in IL-2 [conc.] over time
Immune Biology
 Interleukin-2
• In Adoptive Immunotherapy IL-2 is
administered
 High-dose bolus recombinant IL-2 (600,000
to 720,000 IU/kg IV)
• Acts as a potent immunomodulator and
antitumor element
• Positive results have led approval of
high dose IL-2 for patients with
metastatic melanoma and Renal cell
carcinoma.
• Extensive multiorgan toxicity may occur
Cytokines
Structure of interleukin 2
Fig. 2
Fig. 1
Schematic overview of the high–affinity interleukin–2
receptor complex, including the receptor chains,
downstream signaling components and target genes
Cytokines – IL-2 Targets
 This is a basic overview of the
mechanism of IL-2 activation
Adoptive Immunotherapy
 Technique involves isolating tumorinfiltrating lymphocytes (TIL’s)
• Primarily activated cytotoxic T-lymphocytes
• Lymphocytes with antitumor reactivity found
within the tumor
 Expanding their number artificially in cell
culture by means of human recombinant
interleukin-2.
 The TILs are then put back into the
bloodstream, along with IL-2, where they
can bind to and destroy the tumor cells.
Adoptive Immunotherapy
 Immunotherapy
• IL–2, alone, can be used as a cancer
treatment by activation of cells which
are cytotoxic for the tumor
 Some success has been obtained
with renal cell carcinoma and
metastatic melanoma.
• Rosenburg study
A.I.
This figure
shows adoptive
immunotherapy
isolation
techniques
The Immune Model
The Immune Pathway
Effector Cell
IL-2 Molecules
Think MichaelisMenton
1. IL-2 binds IL-2 Receptor
Step 1
2. Effector Cell with
bound IL-2
Tumor
recognition site
Tumor
cells
IL-2 Receptor
4. Tumor Eating
Site Activated
6. Attack Mode!
Step 6
Step 4
Step 3
Step 5
5. Locates Tumor
3. Effector Cell Activated
And Multiply
The Model
Change in
Effector cells
over time
Antigenicity
and size of
tumor
IL-2
Stimulation
Death
rate
Effector Cell
Injection
Logistic
growth rate
of Tumor
Change in
Tumor cells
Killing rate
by Effector
cells
Change in IL-2
Natural
production of IL-2
Death
rate
IL-2
Injection
Implications of Model
 No Treatment Case
• (1) For very low c, tumor reaches a
stable steady state.
• (2) For intermediate c, tumor has large,
long-period oscillations.
• (3) For high c, tumor has small, lowperiod oscillations.
No Treatment Case - Case 1
 Very low antigenicity.
Days
No Treatment Case – Case 2
 Intermediate antigenicity.
Days
No Treatment Case – Case 3
 High antigenicity.
Days
Implications of Model
With Treatment Case
•(1) A combination of adoptive immunotherapy
with IL-2 is effective for all tumors.
Implications of Model
Implications of Model
(faster!)
Implications of Model
 With Treatment Case
• In high doses, IL-2 therapy leads to a
runaway immune system.
• In low doses, IL-2 therapy has no
qualitative effect on tumor size.
Implications of Model
Reality of IL-2 Therapy
 High-dose IL-2 therapy alone has
been shown to cause a variety of
side effects.
• Generally High Toxicity, e.g. Capillary
Leak Syndrome
 Most of these are explainable by a
runaway immune system.
 Question: IL-2 therapy does work in
some cases; why does the model not
predict this?
Our Contribution
 In reality, once started, IL-2 therapy
is not administered at a constant rate
for all time.
• Rosenberg Study
 (1) Large Bolus Therapy
 (2) Short Duration of Therapy
 (3) Cessation of Therapy upon
appearance of side effects
• We chose to incorporate (3).
Our Contribution
The original model contained a constant term for IL-2 injection; ours
becomes a function of the number of effector cells and time.
Treatment (x,t)
 Treatment continues at a constant rate,
but only until a certain threshold level of
effector cells is reached.
 This simulates the onset of side effects.
 Since the threshold level will vary from patient to
patient, this threshold became a new parameter.
 At that point, treatment ceases and the
model continues with no treatment.
 In addition, the option to delay the start of
therapy for a certain number of days was
implemented.
 This simulates the fact that treatment usually does
not start until the tumor size is large.
Implications of New Model
 For high tumor antigenicity, the
tumor can be cleared by IL-2 therapy
for a relatively low threshold of
immune response.
 The lower the antigenicity, the higher
the threshold needs to be.
 “The nastier the tumor, the tougher the
patient needs to be.”
More animation!
High Antigenicity
(“non-nasty tumor”)
The tumor is eradicated for most values of immune threshold.
More animation!
Medium Antigenicity
(“more nasty tumor”)
The tumor is still eradicated for most values of immune threshold.
Low-Antigenicity Results
 Rosenberg Study
 “Of the 19 patients with complete
regression, 15 have remained in complete
remission from 7 to 91 months after
treatment.”
 Question: Why 7 to 91 months?
 Our model gives a possible
explanation.
Low-Antigenicity Results
 Long-term dormant tumor
 Our model predicts that for low-antigenicity
tumors, IL-2 therapy with most thresholds
of immune response cause the tumor to
enter a dormant, undetectable state.
 During these periods, the qualitative result
is tumor regression.
 However, the tumor re-appears after an
interval on the order of 2700 days,
 … 90 months.
Low-Antigenicity Results
2700 days
For low values of the immune threshold, no long-term change in behavior occurs.
For most values of the immune threshold, a dormant tumor is produced.
For extreme values of the immune threshold, the tumor is eradicated.
Therapy Results - Images
Title: Adoptive-Cell-Transfer Therapy for the Treatment of Patients with
Cancer. Rosenburg SA

Tumor regression by adoptivecell-transfer therapy Activated
T cells can mediate the
regression of a large excess of
metastatic melanoma.

Computed tomography scans
of the trunk and pelvis of one
patient

The regression of bulky
metastases (arrows) in axillary
(top), pelvic (middle) and
mesenteric (bottom) lymph
nodes, mediated by adoptivecell-transfer therapy

Tumour deposits were
present before treatment and
substantially shrank or
completely resolved when
evaluated 8 months later
Therapy Results - Images
 Obtained from a
tumor-bearing host
Title: Adoptive-Cell-Transfer Therapy for the Treatment of Patients with
Cancer. Rosenburg SA

Day 27 before IL-2
therapy (a, b)

Day 63 or 35 days after
IL-2 therapy (c, d)

At positions
comparable to a and b.
Numerous metastases
(0.3 - 2 mm) are
detected before therapy
(a, b).

After successful
therapy with
encapsulation and
rejection of the primary
tumor, the liver was
completely free of
metastases (c, d).
Conclusions

Adoptive Immunotherapy is a technique to manage cancer.

A mathematical model is presented that allows for tumor
regression or predicts the remission time given certain
parameters.

In the case for IL-2 therapy alone the model predicts unbound
behavior.

Actually, clinicians can control when IL-2 is stopped.

We introduce a new parameter Treatment(x,t) that incorporates a
time dimension.

This way we can resolve disparities in actual clinical data and the
predictions of the model.

In general, immunotherapy with IL-2 is on the rise and more
mathematical models will be neccesary to help practitioners
predict future reemergence times in order to restart therapy.
Sources

Rosenberg, SA, Yang, JC, White, DE, et al. Durability of complete responses in patients with
metastatic cancer treated with high-dose interleukin-2: Identification of the antigens mediating
response. Ann Surg 1998; 228:307.

Rosenberg, SA, Yang, JC, Topalian, SL, et al. Treatment of 283 consecutive patients with metastatic
melanoma or renal cell cancer using high-dose bolus interleukin-2. JAMA 1994; 271:907.

Nicola NA (ed) (1994) Guidebook to Cytokines and their Receptors. Oxford: Oxford University Press.

Ostrand–Rosenberg S (1994) Tumor immunotherapy:the tumor cell as an antigen–presenting cell.
Current Opinion in Immunology 6: 722–727.

Rosenberg SA. Lotze MT. Muul LM. Chang AE. Avis FP. Leitman S. Linehan WM. Robertson CN. Lee
RE. Rubin JT. et al. A progress report on the treatment of 157 patients with advanced cancer using
lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. [Journal Article]
New England Journal of Medicine. 316(15):889-97, 1987 Apr 9.

Kirschner D. Panetta JC. Modeling immunotherapy of the tumor-immune interaction. [Journal
Article] Journal of Mathematical Biology. 37(3):235-52, 1998 Sep.

J.C. Arciero, T.L. Jackson, and D.E. Kirschner. A mathematical model of tumor-immune evasion and
siRNA treatment. [Journal Article] Discrete and Continuous Dynamical Systems: Series B. 4(1) 3958, 2004 Feb.

Dudley ME. Rosenberg SA. Adoptive-cell-transfer therapy for the treatment of patients with cancer.
[Review] [97 refs] [Journal Article. Review. Review, Tutorial] Nature Reviews. Cancer. 3(9):666-75,
2003 Sep.

Chang W., Crowl L., Malm E.,Todd-Brown K., Thomas L., Vrable M. Analyzing Immunotherapy and
Chemotherapy of Tumors through Mathematical Modeling. [Book] Department of Mathematics:
Harvey-Mudd University, 2003 Summer.
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